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Global Chromatin Remodeling and Widespread Differential Methylation Changes Underlie Brown Adipose Dysfunction and Dysregulated Metabolism in Response to Chronic Air Pollution Exposure: A Key Role for Reciprocal Regulation by HDAC9 and KDN2b

ABSTRACT: The Global Burden of Disease implicates air pollution in mediating as much as 20% of Type 2 Diabetes mellitus globally. This profound impact of air pollution is supported by experimental studies suggesting effects on whole body metabolism and insulin resistance. We explored the effect of chronic inhalational air pollution exposure for 12 weeks, using a whole body inhalation device in mice that allows for daily exposure to concentrated ambient particulate matter <2.5 microns (6 hours/day, 5 days a week) on whole body metabolism and brown adipose tissue (BAT) function, with detailed investigation of differentially methylated regions (DMRs), chromatin accessibility (differential accessible regions or DARs), and differential gene expression (DEGs) levels using a combination of whole genome bisulfite sequencing, ATAC-sequencing, and RNA-sequencing respectively. A significant impact of chronic PM2.5 exposure on BAT function and whole-body metabolism through alterations in key BAT transcriptional programs resulting in increased redox stress, lipid deposition, fibrosis and reduced thermogenic function of BAT was observed. Significant differential methylation with evidence for both hypomethylation and hypermethylation involving target regions corresponding to both circadian and Nrf2 target genes including sites enriched for transcription factor binding sites implicated in redox stress, insulin resistance and BAT function in response to PM2.5. ATAC sequencing revealed widespread chromatin remodeling involving intronic regions and enhancer elements and loss of DARs in Ucp1 and Gclc major regulatory genes associated with thermogenesis and glutathione synthesis. DARs-DEGs interaction analysis pointed to functional pathways linked to diabetes development, fatty acid biosynthesis activation and activation of JAK-STAT, and MAPK in PM-exposed mice. Integrated analysis of DARs, DEGs and DMRs uncovered the Histone de-acetylase Hdac9 and Kdm2b, a Histone demethylase that demethylates 'Lys-4' and 'Lys-36' of histone H3. ChiP studies demonstrated that Hdac9 physically interacts with the BAT transcription factor Prdm16 and rorα in BAT decreasing their expression and providing at least one direct mechanism for our observations. Collectively our results results link DNA methylation with control of chromatin accessibility and gene expression changes involved in the alteration of brown fat metabolism linking chronic air pollution exposure with alterations in BAT and whole-body metabolism

ORGANISM(S): Mus musculus

PROVIDER: GSE255961 | GEO | 2025/07/30

REPOSITORIES: GEO

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Project description:Background: Epidemiologic associations between acutely increased cardiorespiratory morbidity and mortality and particulate air pollution are well-established, but the effects of acute pollution exposure on human gene expression changes are not well understood. Objectives: In order to identify potential mechanisms underlying epidemiologic associations between air pollution and morbidity, we explored changes in gene expression in humans following inhalation of fresh diesel exhaust (DE), a model for particulate air pollution. Methods: 14 ethnically homogeneous (white males), young, healthy subjects underwent sixty minute inhalation exposures on 2 separate days with clean air (CA) or freshly generated and diluted DE at a concentration of 300 Î¼g/m3 PM2.5. Prior to and 24 hours following each session, whole blood was sampled and fractionated for PBMC isolation, RNA extraction, and generation of cDNA, followed by hybridizationÂ withÂ Agilent Whole Human Genome (4X44K) arrays. Results: Oxidative stress and the ubiquitin proteasome pathway, as well as the coagulation system, were among hypothesized pathways identified by analysis of differentially expressed genes. Nine genes from these pathways were validated using real-time PCR comparing fold change in expression between DE exposed and clean (CA) days. Quantitative gene fold changes generated by real-time PCR were consistent with the directional fold changes from the microarray analysis. Conclusions: Changes in gene expression connected with key oxidative stress, protein degradation, and coagulation pathways are likely to underlie observed physiologic and clinical outcomes and suggest specific avenues and sensitive time points for further physiologic exploration. Diesel exhaust inhalation exposure-induced human gene expression changes were measured in peripheral blood mononuclear cells. 14 white males subjects were seated in a controlled environment facility for 2 separate 60 minute inhalation exposures which occurred at least 1 week apart to either clean air and freshly generate or diluted diesel exhaust (300ug/m3 PM2.5) .Blood collection occurred immediately prior to and 24 hours following exposures. Two microarrays per subject were completed using Agilent Whole Human Genome (4X44K) arrays. Genes that were of interest to our research group were verified using Real Time PCR analysis.

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Global Chromatin Remodeling and Widespread Differential Methylation Changes Underlie Brown Adipose Dysfunction and Dysregulated Metabolism in Response to Chronic Air Pollution Exposure: A Key Role for Reciprocal Regulation by HDAC9 and KDN2b

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